The botanical family Simaroubaceae includes numerous species distributed primarily in pantropical regions. These plant species have been the source of a large family of bitter terpenoid substances collectively termed quassinoids. Like many plant alkaloids or naturally isolated plant extracts, quassinoids have been found to have diverse biologic activity, including anti-malarial, anti-insecticidal, anti-amoebicidal, anti-leukemic, and anti-viral activity.
The great majority of quassinoids are heavily oxygenated lactones that include the following twenty carbon skeleton, ##STR1## conventionally termed picrasane, although eighteen, nineteen, and twenty-five carbon skeletons are also known. Many variant ring structures and sidechains, particularly at C-15, are known (See eg. Polonsky, "Quassinoid Bitter Principles II", Fortschr.Chem.Org Naturst, Progress in the Chemistry of Organic Natural Products, 1985, 47, 221). The present invention includes both novel and synthetically derived quassinoid analogs, as well as novel uses for such synthetic quassinoids and previously identified and isolated natural quassinoids. In one aspect of the present invention, disclosed is a compound characterized by the formula ##STR2## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycosaccharides, water soluble sidechains, amino acid, peptide, and any of the foregoing attached at C-15 by an ether, ester, carbonyl, or glycosidic linkage.
In preferred embodiments, the sidechain Y is represented by the formula ##STR3## wherein R.sub.2, R.sub.3, and R.sub.4 taken separately or together represent hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains, amino acids, peptide, and any of the foregoing attached to the central carbon by an ether, ester, carbonyl, or glycosidic linkage.
Specific embodiments of the present invention include those wherein R.sub.2 is a methyl group, R.sub.3 is a methyl group, and R.sub.4 is a hydroxyl group, those wherein R.sub.2 is a methyl group, R.sub.3 is a methyl group, and R.sub.4 is a hydroxyalkane, hydroxyalkene, glycyl, glycosaccharides, or water soluble sidechain, or those wherein R.sub.2 is an ethyl group, R.sub.3 is a hydroxyl group, and R.sub.4 is an ethyl group. In addition, compounds wherein R.sub.2 is a methyl group, R.sub.3 is a methyl group, and R.sub.4 is a hydroxymethyl group, or wherein R.sub.2 is a methyl group, R.sub.3 is a methyl group, and R.sub.4 is a methyl group are included in the scope of the present invention.
Alternatively, the Y sidechain of Formula III above can be modified to support ring structures such as aryls or cycloalkanes. For example, R.sub.2 and R.sub.3 taken together can form a C.sub.3 to C.sub.8 membered carbon ring, and R.sub.4 substituted with a hydroxymethyl group. More specifically, R.sub.2 and R.sub.3 can be taken together form a three membered cycloalkane, with R.sub.4 being a hydroxymethyl group.
In still other embodiments, the sidechain Y can be represented as ##STR4## wherein R.sub.5, R.sub.6, and R.sub.7 taken separately or together represent hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, or water soluble sidechains, amino acids, peptide, and any of the foregoing attached to the terminal carbon by an ether, ester, carbonyl, or glycosidic linkage.
More specifically, embodiments of the present invention wherein R.sub.5 is an isopropyl group, R.sub.6 is an isopropyl group, and R.sub.7 is a hydroxyl group; wherein R.sub.5 and R.sub.6 taken together comprise a double bonded carbon group, and R.sub.7 is a methyl group; or wherein R.sub.5 is a hydrogen, R.sub.6 is a hydrogen, and R.sub.7 is a carboxyl group are contemplated as within the scope of the present invention.
In addition, cyclic ring structures wherein R.sub.5 and R.sub.6 taken together form a C.sub.3 to C.sub.8 membered carbon ring, and R.sub.7 further comprises hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains, amino acids, peptide, and any of the foregoing attached to the terminal R.sub.7 carbon by an ether, ester, carbonyl, or glycosidic linkage are within the scope of the present invention. More specifically, those embodiments wherein R.sub.5 and R.sub.6 taken together form a four membered cycloalkane, and R.sub.7 is a hydroxyl group; wherein R.sub.5 and R.sub.6 taken together form a five membered cycloalkane, and R.sub.7 is a hydroxyl group; wherein R.sub.5 and R.sub.6 taken together form a six membered cycloalkane, and R.sub.7 is a hydroxyl group; wherein R.sub.5 and R.sub.6 taken together form a seven membered cycloalkane, and R.sub.7 is a hydroxyl group; wherein R.sub.5 and R.sub.6 taken together form a four membered cycloalkane, and R.sub.7 comprises a group having the formula ##STR5## are considered to be within the scope of this invention.
Still other embodiments of the present invention also include the compound of formula IV above, wherein R.sub.5 and R.sub.6 taken together comprise a double bonded carbon group, and together with R.sub.7 form a five membered cycloalkene. Alternatively, the sidechain Y of the compound represented by Formula II can be represented as ##STR6## wherein R.sub.8 and R.sub.9 taken separately or together represent hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, glycine, glycosaccharides, water soluble sidechains, amino acids, peptide, and any of the foregoing attached to the terminal carbon by an ether, ester, carbonyl, or glycosidic linkage. More specifically, those embodiments of the present invention wherein R.sub.8 is a methyl group and R.sub.9 is a methyl group; or wherein R.sub.8 is an isopropyl group and R.sub.9 is an isopropyl group are within the scope of the present invention.
Another aspect of the present invention is the use of the foregoing described synthetically derived quassinoids, or previously known, purified and isolated quassinoids, for the treatment in conjunction with suitable pharmaceutical carriers of neoplastic disorders such as solid tumors. For example, a chemotherapeutic composition for treatment of cancer can comprise a combination of a compound characterized by the formula ##STR7## wherein R.sub.1 represents hydrogen, oxygen, alkyl, alkenyl, acyl, aryl, halogen, sulfo, nitro, carboxyl, hydroxyl, hydroxyalkyl, alkoxy, or other water soluble sidechain, and Y is a sidechain comprising hydrogen, alkyl, hydroxyalkyl, carboxyl, aryl, alkenyl, cycloalkanes, cycloalkenes, water soluble sidechains, amino acids, peptide, and any of the foregoing attached to the terminal carbon by an ether, ester, carbonyl, or glycosidic linkage, and a pharmaceutically acceptable carrier therefor. As will be appreciated by those skilled in the art, the particular pharmaceutical carrier can be saline solution incorporating suitable stabilants, buffers, antimicrobial agents, antifungal agents, or other such additions as required for storage and delivery. In addition, the present invention contemplates lyophilized storage, with activation upon mixing, or any other storage technique known and utilized by those skilled in the pharmaceutical arts.
Still another aspect of the present invention is the use of the foregoing described synthetically derived quassinoids, or previously known, purified and isolated quassinoids, for treatment in conjunction with suitable pharmaceutical carriers of viral infections. Viral infections may include rhinoviruses, pseudorabies, or retroviral infections such as human immunodeficiency virus (HIV). Advantageously, certain compounds according to the present invention are believed to preferentially target virally infected cells, instead of acting against isolated viral particles.
As will be appreciated by those skilled in the art, the particular pharmaceutical carrier for use in conjunction with the antiviral compounds of the present invention can be saline solution incorporating suitable stabilants, buffers, antimicrobial agents, antifungal agents, or other such additions as required for storage and delivery. In addition, the present invention contemplates lyophilized storage, with activation upon mixing, or any other storage technique known and utilized by those skilled in the pharmaceutical arts.
Another aspect of the present invention is the preparation of an impermeant quassinoid conjugate that is active against a cancer-specific isoform of a plasma membrane NADH oxidase (tNOX) with characteristics of pancancer anticancer agents. Its use or use of conjugates of other members of the quassinoid series as broad-spectrum anticancer drugs is indicated.
The opportunities for conjugation are broad. The principal requirements are that the conjugating materials render the quassinoid impermeant and do not interfere with its ability to inhibit growth through the cell surface site. Additionally, the materials having therapeutic utility would be expected to benefit from being non-toxic and non-immunogenic and should result in conjugates that are water soluble and/or easy to administer. Active species in high yield and efficacy at low cost would constitute additional desirable properties.
Examples of suitable conjugating materials include polyethyleneglycol, dextran, dextrins, carboxymethylcellulose, polyoxyethylene/polyoxypropylene (polyoxamine) blockpolymers, polyglutamine and other polyamines, N-(2-hydroxypropyl)methacrylamide copolymers, and other polymers properly functionalized to allow facile and functional conjugate formation. The degree of polymerization of the polymer in the polymeric-drug conjugate may vary from N=1 to N=1000 or more as long as the final conjugate is impermeant, effective and is able to reach the target site to deliver therapeutic levels of drug. The linkage may be non-hydrolyzable or hydrolyzable and may contain one or more space atoms optimized to enhance efficacy.
To aid in effective delivery of an anticancer or antiviral agent of the present invention to a desired body site, targeting agents such as monoclonal antibodies, chemical compounds differentially uptaken by cancerous or virally infected cells, or agents known to target cancerous or virally infected tissue (eg. hepatic tissue targeted by acetaminophen derivatives or glycosaccharides) can be conjugated to the compounds of the present invention. As those skilled in the art will appreciate, intravenous delivery is preferred, although topical, oral, or subcutaneous delivery may also be appropriate in specific situations.
In order to prepare conjugates that impact specificity of targeting, quassinoids can be combined variously with, for example, proteins, antibodies, nucleic acids, or even lipids or derivatized polymeric substances and various naturally occurring macromolecules such as immunoglobulins, growth hormones, insulin, interferons, plasma albumin, fibrinogen, plasminogen activator, heparin, chondroitin sulfate, soybean trypsin inhibitor, L-asparaginase, ribonuclease, etc. that would function as homing receptors or targets to a specific cell type (e.g., cancer cells) or location (e.g., bone marrow).
One more aspect of the present invention is the use of the foregoing described synthetically derived quassinoids, or previously known, purified and isolated quassinoids, for use as an NADH oxidase inhibitor. This use is believed to account for differential cytotoxicity of compounds according to the present invention, as well as for herbistatic activity of the compounds.
Additional objects, features, and advantages of the present invention will be apparent upon consideration of the following detailed description and accompanying drawings.